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Objective  Dimethyl fumarate ( DMF ) is a fumaric acid ester approved for the treatment of relapsing‐remitting multiple sclerosis ( RRMS ). In both the brain and periphery,  DMF  and its metabolite monomethyl fumarate ( MMF ) exert anti‐inflammatory and antioxidant effects. Our aim was to compare the effects of  DMF  and  MMF  on inflammatory and antioxidant pathways within astrocytes, a critical supporting glial cell in the central nervous system ( CNS ). Direct effects of fumarates on neural progenitor cell ( NPC ) differentiation toward the oligodendrocyte lineage were also assessed.    Methods  Primary astrocyte cultures were derived from both murine and human brains. Following pretreatment with  MMF ,  DMF , or vehicle, astrocytes were stimulated with  IL ‐1 β  for 24 h; gene and micro RNA  expression were measured by  qPCR . Cytokine production and reactive oxygen species ( ROS ) generation were also measured.  NPC s were differentiated into the oligodendrocyte lineage in the presence of fumarates and immunostained using early oligodendrocyte markers.    Results  In both murine and human astrocytes,  DMF , but not  MMF , significantly reduced secretion of  IL ‐6,  CXCL 10, and  CCL 2; neither fumarate promoted a robust increase in antioxidant gene expression, although both  MMF  and  DMF  prevented intracellular  ROS  production. Pretreatment with fumarates reduced micro RNA s ‐146a and ‐155 upon stimulation. In  NPC  cultures,  DMF  increased the number of O4 +  and  NG 2 +  cells.    Interpretation  These results suggest that  DMF , and to a lesser extent  MMF , mediates the anti‐inflammatory effects within astrocytes. This is supported by recent observations that in the inflamed  CNS ,  DMF  may be the active compound mediating the anti‐inflammatory effects independent from altered antioxidant gene expression.

Effects of fumarates on inflammatory human astrocyte responses and oligodendrocyte differentiation